Abstract 4324: Inhibition of ERK reactivation by FGTI-2734: A strategy to overcome sotorasib resistance in KRAS G12C lung cancer

Abstract Discovery of sotorasib is a major breakthrough for KRAS G12C targeted therapies. However, overall response rates of patients with KRAS G12C lung cancer treated with sotorasib are modest due to resistance mediated by adaptive reactivation of ERK, which requires wild-type (WT) RAS membrane localization. In this study, we demonstrate that the dual farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT-1) inhibitor FGTI-2734 inhibits WT RAS membrane localization, and overcomes sotorasib adaptive resistance through inhibition of sotorasib-induced ERK feedback reactivation. The combination of FGTI-2734 and sotorasib is synergistic at inhibiting the viability and inducing apoptosis of lung cancer cell lines with KRAS G12C mutation, including those that are highly resistant to sotorasib. Anti-tumor activity of sotorasib is enhanced by FGTI-2734, leading to significant tumor regression of a patient-derived xenograft (PDX) from a KRAS G12C lung cancer patient as well as several xenografts from highly sotorasib-resistant KRAS G12C human lung cancer cells. Importantly, in vivo, FGTI-2734 inhibited sotorasib-induced ERK reactivation in the KRAS G12C PDX, and combinations of FGTI-2734 and sotorasib were also significantly more effective at suppressing the levels of P-ERK in sotorasib-resistant human KRAS G12C lung cancer xenografts. This study provides a rational strategy for overcoming sotorasib resistance in KRAS G12C lung cancer. Citation Format: Aslamuzzaman Kazi, Hitesh Kumar Kantilal Vasiyan, Deblina Ghosh, Dipankar Bandyopadhyay, Rachit D. Shah, Vignesh Vudatha, Jose Trevino, Said M. Sebti. Inhibition of ERK reactivation by FGTI-2734: A strategy to overcome sotorasib resistance in KRAS G12C lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4324.